The compounds of the formula (I) according to the invention are new and possess a significant antioxidant (lipid peroxidation-inhibiting) effect. Thus, they are therapeutically useful.
There are a high number of pathologic processes known in the case of which extremely reactive free oxygen radicals (O.sub.2.sup.-2) are accumulated. The formation of these free radicals leads to the oxidation of unsaturated fatty acids (lipid peroxidation) which are important components of the cell membranes. This is a less specific, cell-destroying process, altering or damaging the biomolecules. In this process, functions of various levels of cells, organs or the whole organism may suffer injuries.
Free radical reactions likely play a causal role in the pathogenesis of ischaemia-induced injuries such as ischaemic intestinal diseases, myocardial ischaemia, haemorrhagic shock, cerebrovascular function disturbances accompanied by ischaemia and renal ischaemia R. J. Korthuis et al.: "Physiology of Oxygen Radicals", Chapter 17, pages 217-249 (1986)!.
Due to their lipid peroxidation-inhibiting effect, antioxidative compounds assure protection against injuries induced by free radicals under ischaemic, hypoxic conditions. Thus, antioxidants as antiischaemic and antihypoxic compounds can be used for the treatment of such clinical pictures.
It can be considered to be proven that free radical reactions play a partial role in the development of symptoms of diseases of the connective tissues and a primary aetiological role in rheumatoid arthritis J. Lunec et al.: "Cellular Antioxidant Defense Mechanisms", Chapter 33, pages 143-159 (1988) (CRC Press Inc., Boca Raton, Fla., 1988)!.
There are several hepatotoxic substances known, the liver-damaging effect of which is presumably a consequence of pathologic free radical reactions. Thus, antioxidative compounds may provide protection against acute and chronic diseases of the liver J. Feher and A. Vereckei: "The Importance of Free Radical Reactions in Medicine" (in Hungarian), pages 99-104 (Editory Medicina, Budapest, 1985)!.
It has essentially been proven that free radical reactions play a role in several haematologic clinical pictures such as sickle-cell anaemia and beta-thalassaemia (Mediterranean anaemia).
Due to the diminished defense ability, O.sub.2 therapy or phototherapy, respectively, may further increase the risk of oxidative injuries in the cases of newburn or premature infants. The use of some antioxidants proved to be favorable in the treatment of such clinical pictures.
Lipid peroxidation occurring as a consequence of injuries is a secondary process. Some cells are immediately destroyed by the injury, which then extends also to the surrounding cells in the next following hours. This is also caused by free oxygen radicals which attack the lipid layer of the cell membrane and can eventually lead to cell death by injuring the membrane and releasing hydrogen peroxide. Lipid peroxidation-inhibiting compounds are capable to prevent this secondary process. Thus, they can be used for stopping degenerative processes occurring as a consequence of cephalic and spinal injuries. Compounds having such an effect can be utilized also in the treatment of Alzheimer's disease, muscular dystrophy and the like.
The importance of lipid peroxidation-inhibiting compounds is supported also by the great number of the most recent literature data, patent applications and scientific publications.
In the published PCT patent application No. WO 87/01706, mainly the preparation of aminosteroids is described, where an amino group is bound to the terminal carbon atom of the C.sub.17 side chain. Double bond(s) is (are) present in position(s) 4 or 1,4 of ring A of the steroid skeleton whereas an oxo or hydroxyl group in position 3, an .alpha.- or .beta.-alkyl group or halogen in position 6, mainly an .alpha.-hydroxyl group in position 11, an .alpha.- or .beta.-methyl group in position 16 and a double bond in position 9(11) are present. The ring A of the steroid skeleton may be saturated or aromatic, too. A few 21-aminosteroids are also described, wherein the double bond takes place in position 17(20). In most cases, the disubstituted pyrimidine, triazine or pyridine cycle is connected through a piperazinyl group to position 21 of the compounds according to this publication. Among the compounds published 16.alpha.-methyl-21-{4- 2,4-bis(pyrrolidino)-6-pyrimidinyl!-1-piperazinyl} -pregna-1,4,9(11)-triene-3,20-dione methanesulfonate (tirilazad mesylate) is in the second stage of clinical trials at present.
Similarly, the synthesis of lipid peroxidation-inhibiting compounds containing asteroid skeleton is described in the published PCT patent application No. WO 87/07895, where mainly the preparation of steroid amino esters and corticoid amino esters, especially 17-amino esters, 11,17-bis(amino) esters, 3,17-bis(amino) esters, 11-amino esters and 3-amino esters is discussed. According to this patent application the above derivatives can be used for inhibiting the lipid peroxidation occurring as a consequence of spinal, cephalic and other injuries. The structure of amino substituents is similar to that described in the preceding publication.
The preparation of novel amino-9,10-secosteroids is described in the published PCT patent application No. WO 88/07527. The amino substituent is connected to the terminal carbon atom of the C.sub.17 side chain of the secosteroid. The amino substituents are the same as those described in the preceding publications.
The synthesis of lipid peroxidation-inhibiting compounds is described also in the published. European patent applications Nos. 0,389,368, 0,389,369 and 0,389,370 as follows.
The preparation of corticoid-type 21-aminosteroids is disclosed in the application No. 0,389,368. For example, a 4- 2,5-bis(diethylamino)-6-pyridinyl!piperazinyl group may be bound to the C.sub.21 carbon atoms. The steroid skeleton contains one or two double bond(s) in the ring A, whereas the substituents being characteristic of the corticoids may be present in positions 6, 9, 11, 16 and 17. A double bond may be present in position 9(11), too.
The synthesis of amine derivatives of 3-oxo-19-norsteroids is described in the patent application No. 0,3S9,370 wherein
17.beta.-hydroxy-11.beta.-(4-dimethylaminophenyl)-17.alpha.-{3- 4-(2,6-bis- (pyrrolidino)-4-pyrimidinyl)-1-piperazinyl!-1-propynyl}-estra-4,9-dien-3-on e, PA0 17.beta.-hydroxy-11.beta.-(4-dimethylaminophenyl)-17.alpha.-{3- 4-(5,6-bis- (diethylamino)-2-pyridyl)-1-piperazinyl!-1-propynyl}-estra-4,9-dien-3-one, PA0 17.beta.-hydroxy-11.beta.-(4-dimethylaminophenyl)-17.alpha.-{3- 4-(3,6-bis- (diethylamino)-2-pyridyl)-1-piperazinyl!-1-propynyl}-estra-4,9-dien-3-one, PA0 17.beta.-hydroxy-11.beta.-(4-dimethylaminophenyl)-17.alpha.-{3- 4- 2,6-bis- (1-pyrrolidinyl)-4-pyrimidinyl!-1-piperazinyl!-1-propenyl}estra-4,9-dien-3- one and PA0 17.beta.-hydroxy-11.beta.-(4-dimethylaminophenyl)-17.alpha.-{3- 4- 2,6-bis- (pyrrolidino)-4-pyrimidinyl)-1-piperazinyl!-1-propyl}-estra -4,9-dien-3-one are named as compounds prepared. PA0 1: 1- (3.alpha.,16.alpha.)-eburnamenine-14-carbonyl!-4- 2,6-bis(pyrrolidino)- 4-pyrimidinyl!piperazine PA0 2: 1-{ (3.alpha.,16.alpha.)-eburnamenine-14-yl!methyl}-4- 2,6-bis(pyrrolidino )-4-pyrimidinyl!piperazine trihydrobromide PA0 3: 1- (16.alpha.)-eburnamenine-14-carbonyl!-4- 2,6-bis(pyrrolidino)-4-pyrimid inyl!piperazine PA0 4: 1- (3.alpha.)-eburnamenine-14-carbonyl!-4- 2,6-bis(pyrrolidino)-4-pyrimidi nyl!piperazine
In the patent application Ser. No. 0,389,369 the synthesis of aminosteroid derivatives containing an androstane skeleton is described, which similarly possess a lipid peroxidation-inhibiting effect. Such compounds are e.g. 11.beta.,17.beta.-dihydroxy-17.alpha.-{3- 4- 2,6-bis(pyrrolidino)-4-pyrimi dinyl)-1-piperazinyl!-1-propynyl}-androsta-4,6-dien-3-one, 11.beta.,17.beta.-dihydroxy-6-methyl-17.alpha.-{3- 4- 2,6-bis(pyrrolidino) -4-pyrimidinyl!-1-piperazinyl!-1-propynyl}-andostra-1,4,6-trien-3-one, 11.beta.,17.beta.-dihydroxy-6-methyl-17.alpha.-{3- 4- 5,6-bis(diethylamino )-2-pyridyl!-1-piperazinyl!-1-propynyl}-andostra-1,4,6-trien-3-one and 11.beta.,17.beta.-dihydroxy-6-methyl-17.alpha.-{3- 4- 3,6-bis(diethylamino )-2-pyridyl!-1-piperazinyl!-1-propynyl}-andostra-1,4,6-trien-3-one.
In the published European patent application No. 0,156,643 mainly the preparation of water-soluble corticosteroid derivatives is reported, the main characteristic of which is that a hydroxyl group or an esterified hydroxyl group stands in the .alpha.-position or a double bond is present in position 9(11). From the compounds discussed, sodium 17.alpha.-hydroxy-11.alpha.-(2,2-dimethylpropylcarbonyloxy)-pregna-1,4-di en-3,20-dion-21-yl!succinate is considered to be the most active lipid peroxidation-inhibiting compound.
In the published PCT application No. WO 91/11453 bis-("amino")pyrimidinyl-piperazinyl derivatives containing an oxygen function in position 5 are disclosed, in the case of which asteroid molecule or a 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ylmethyl group or a derivative thereof may be connected to the nitrogen atom in position 1 of the piperazine moiety. Alkyl-substituted 5-hydroxypyrimidine derivatives are also described in this patent application.
Logically, the research in the field of lipid peroxidation-inhibiting compounds has been extended also to the investigation of amine derivatives containing no steroid skeleton. Thus, e.g. in the published PCT patent application No. WO 88/08424 the preparation of novel aromatic and aliphatic bicyclic amine, cycloalkylamine, quinone-amine, amino ether and bicyclic amino ether derivatives are described, which may be useful for the healing of cephalic and spinal injuries. Of the derivatives described 2-{ 4- 2,6-bis(pyrrolidino)-4-pyrimidinyl!-1-piperazinyl!-methyl}-3,4-dihy dro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol dihydrochloride has been subjected to detailed investigations.